ZAFIBRAL Film-coated tablet Ref.[28168] Active ingredients: Bezafibrate

See also “Preclinical Safety Data”.

Bezafibrate could cause cholelithiasis, although there is no evidence of an increased frequency of gallstones in patients treated with Zafibral. Appropriate diagnostic procedures should be performed if cholelithic symptoms and signs occur (see section 4.8 Undesirable effects).

Muscle effects: Bezafibrate and other fibrates may cause myopathy, manifested as muscle weakness or pain, often accompanied by a considerable increase in creatine kinase (CPK). In isolated cases severe muscle damage (rhabdomyolysis) may occur. The risk of rhabdomyolysis may be increased in patients with predisposing factors for myopathy (including renal impairment, hypothyroidism, severe infections, trauma, surgery, disturbances of hormone or electrolyte imbalance and a high alcohol intake.

Bezafibrate should be used with caution in combination with HMG CoA reductase inhibitors as the combination of HMG CoA inhibitors and fibrates has been shown to increase the incidence and severity of myopathy. Patients should be monitored for signs of myopahty and increased CPK activity and combination therapy discontinued if signs of myopahty develop. Combination therapy should not be used in patients with predisposing factors for myopathy (see section 4.5 Interaction with other medicaments and other forms of interaction).

Anticoagulants

The action of coumarin type anticoagulants may be potentiated by concurrent bezafibrate administration, and care is necessary in such patients. Reduction of anticoagulant dosage by up to half, followed by readjustment by monitoring of blood coagulation is recommended.

Antidiabetic medication

Glucose utilisation is improved by bezafibrate, and therefore antidiabetic agents, including insulin, may be potentiated. Although hyperglycaemia has not been reported increased monitoring of glycaemic status for a short period following bezafibrate therapy introduction is recommended.

Cyclosporin

Isolated instances of a significant, although reversible, impairment of renal function in association with a corresponding serum creatinine level elevation have been reported in organ transplant patient undergoing cyclosporin with concurrent bezafibrate therapy. In such patients the renal function should be closely monitored and should relevant significant changes in laboratory values be observed, bezafibrate should be withdrawn if necessary.

Ion exchange resin

In the event of combination therapy with ion exchange resin and bezafibrate, the dosage of ion exchange resin and bezafibrate must be separated by two hours or bezafibrate absorption may be impaired.

HMG CoA Reductase Inhibitors / Fibric acid derivatives

Combination therapy has been reported to increase the risk of myopathy and therefore such combination therapy should be undertaken with caution. Close monitoring of patients for elevation of creatine kinase activity and signs of myopathy is required. Patients with predisposing risk factors for myopathy, hormone disturbances, electrolyte imbalance, severe infection, surgery or trauma, and impaired renal function, should not be administered such combination therapy.

Monoamine Oxidase Inhibitors (MAOIs)

Administration of MAOIs with hepatoxic potential concurrently with bezafibrate is contraindicated.

Oestrogens

Oestrogen administration may lead to an elevation of lipid levels, therefore careful individual consideration should be given as to the necessity for bezafibrate administration in patients receiving oestrogens or oestrogen containing preparations.

Pregnancy

Animal studies have shown no evidence of adverse effects on the foetus, however such studies are not always indicative of behaviour in man. There are no adequate and well controlled studies in man. Bezafibrate administration is not recommended in pregnancy.

Lactation

It is unknown whether bezafibrate is excreted in breast milk. Bezafibrate administration is not recommended during breast feeding.

Bezafibrate has no known effects on the ability to drive or operate machinery.

The majority of adverse effects are generally reversible following the withdrawal of bezafibrate therapy.

Central Nervous System: there are rare reports of headache, occasionally recurrent, and dizziness and insomnia.

Dermatological: rare reports of alopecia.

Gastrointestinal: occasional reports of loss of appetite, fullness of stomach and nausea. Such effects are generally transient and do not usually necessitate therapy withdrawal. Alleviation, or avoidance of such symptoms in susceptible patients may be facilitated by incremental dosage increases over a period of about a week.

Haematological: isolated reports of reduction of haemoglobin and leucocytes. Both thrombocytopenia which may cause bleeding, resulting in purpura and pancytopenia have also been reported in isolated instances.

Hepatological: elevations of transaminases, cholestasis and fallstones have been reported in some instance (see also “Special warnings and Special Precaustions for Use”).

Immunological: there are occasional reports of allergic skin reactions, including pruritus and urticaria. Photosensitivity or generalised hypersensitivity reactions may occur in isolated instances.

Musculoskeletal: muscular weakness, muscle cramps and myalgia in many instances accompanies by significant elevations of creatine kinase, may occur. In some isolated instances rhabdomyolysis has been observed and in such instances bezafibrate therapy must be promptly withdrawn and renal function must be closely monitored.

Urino-genital: there are isolated instances of sexual dysfunction, impotence or libido reduction reported. Libido reduction may be associated with mild hyperprolactinaemia, although the association can not be confirmed.

Not applicable.